Tetrahydro-Naphthalene Derivatives as Vanilloid Receptor Antagonists

Abstract

This invention relates to tetrahydro-naphthalene derivatives and salts thereof which is useful as an active ingredient of pharmaceutical preparations. The tetrahydronaphthalene derivatives of the present invention have an excellent activity as VR1 antagonist and useful for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urinary incontinence, urge urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, inflammatory disorders, asthma and COPD.

1 - 21 . (canceled) 
   
   
       22 . A method of treating a urological disorder or disease in a subject comprising administering to the subject an effective amount of a compound of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 n represents an integer of 0 to 6; 
 R 1  represents hydrogen or C 1-6  alkyl; 
 R 2  and R 3  together with the nitrogen atom to which they are attached, form a 3-8 membered saturated heterocyclic ring optionally interrupted by one or two atoms selected from the group consisting of oxygen, sulfur and nitrogen, 
 wherein said saturated heterocyclic ring has one or more substituents selected from the group consisting of halogen, benzyl, hydroxy, carboxy, amino, oxo, aminocarbonyl, C 1-6  alkoxycarbonyl, and C 1-6  alkyl optionally substituted by hydroxy, carboxy, C 1-6  alkoxy, or C 1-6  alkoxycarbonyl, or 
 R 2  represents C 2-6  alkenyl, C 2-6  alkynyl, or C 1-6  alkyl substituted by amino, hydroxy, C 1-6  alkylamino, or di(C 1-6  alkyl)amino; 
 R 3  represents hydrogen, C 2-6  alkenyl, C 2-6  alkynyl, or C 1-6  alkyl optionally substituted by amino, hydroxy, C 1-6  alkylamino, or di(C 1-6  alkyl)amino; and 
 R 4  represents hydrogen, halogen, C 1-6  alkylthio, C 1-6  alkyl optionally substituted by mono-, di-, or tri-halogen, or C 1-6  alkoxy optionally substituted by mono-, di-, or tri-halogen. 
 
   
   
       23 . The method of  claim 22 , wherein the urological disorder or disease is selected from the group consisting of urinary incontinence, urge urinary incontinence and overactive bladder. 
   
   
       24 . The method of  claim 22 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached, form a 5-7 membered saturated heterocyclic ring optionally interrupted by one or two atoms selected from the group consisting of oxygen and nitrogen. 
   
   
       25 . The method of  claim 22 , wherein the compound is selected from the group consisting of: 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-piperidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4-pyrrolidin-1-yl-3-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-pyrrolidin-1-yl-4-(-trifluoromethyl)benzyl]urea; 
     N-[4-azepan-1-yl-3-(trifluoromethyl)benzyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-[3-azepan-1-yl-4-(trifluoromethyl)benzyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-(3-bromo-4-piperidin-1-ylbenzyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-[(7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4-piperidin-1-yl-3-(trifluoromethyl)benzyl]urea; 
     ethyl 1-[5-[({[(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)amino]carbonyl}amino)-methyl]-2-(trifluoromethyl)phenyl]piperidine-4-carboxylate; 
     N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-morpholin-4-yl-4-(trifluoromethyl)benzyl]urea;
 a tautomeric or stereoisomeric form of any of the foregoing compounds; and 
 a salt of any of the foregoing compounds. 
 
   
   
       26 . The method of  claim 22 , wherein the compound is N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea, in its tautomeric or stereoisomeric form, or a salt thereof. 
   
   
       27 . The method of  claim 22 , wherein the compound is N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-morpholin-4-yl-4-(trifluoromethyl)benzyl]urea, in its tautomeric or stereoisomeric form, or a salt thereof. 
   
   
       28 . A method of treating pain in a subject comprising administering to the subject an effective amount of a compound of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 n represents an integer of 0 to 6; 
 R 1  represents hydrogen or C 1-6  alkyl; 
 R 2  and R 3  together with the nitrogen atom to which they are attached, form a 3-8 membered saturated heterocyclic ring optionally interrupted by one or two atoms selected from the group consisting of oxygen, sulfur and nitrogen, 
 wherein said saturated heterocyclic ring has one or more substituents selected from the group consisting of halogen, benzyl, hydroxy, carboxy, amino, oxo, aminocarbonyl, C 1-6  alkoxycarbonyl, and C 1-6  alkyl optionally substituted by hydroxy, carboxy, C 1-6  alkoxy, or C 1-6  alkoxycarbonyl, or 
 R 2  represents C 2-6  alkenyl, C 2-6  alkynyl, or C 1-6  alkyl substituted by amino, hydroxy, C 1-6  alkylamino, or di(C 1-6  alkyl)amino; 
 R 3  represents hydrogen, C 2-6  alkenyl, C 2-6  alkynyl, or C 1-6  alkyl optionally substituted by amino, hydroxy, C 1-6  alkylamino, or di(C 1-6  alkyl)amino; and 
 R 4  represents hydrogen, halogen, C 1-6  alkylthio, C 1-6  alkyl optionally substituted by mono-, di-, or tri-halogen, or C 1-6  alkoxy optionally substituted by mono-, di-, or tri-halogen. 
 
   
   
       29 . The method of  claim 28 , wherein the pain is selected from the group consisting of chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, musculoskeletal pain, back pain, orofascial pain, headache, visceral pain, pelvic pain, vulvodynia, orchialgia and prostatodynia. 
   
   
       30 . The method of  claim 28 , wherein the pain is pain associated with a disease or disorder. 
   
   
       31 . The method of  claim 30 , wherein the disease or disorder is selected from the group consisting of neuralgia, a neuropathy, algesia, nerve injury, ischaemia, neurodegeneration, stroke, arthritis, cancer, irritable bowel syndrome and inflammatory lesions of joints, skin, muscles and nerves. 
   
   
       32 . The method of  claim 28 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached, form a 5-7 membered saturated heterocyclic ring optionally interrupted by one or two atoms selected from the group consisting of oxygen and nitrogen. 
   
   
       33 . The method of  claim 28 , wherein the compound is selected from the group consisting of: 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-piperidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4-pyrrolidin-1-yl-3-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-pyrrolidin-1-yl-4-(-trifluoromethyl)benzyl]urea; 
     N-[4-azepan-1-yl-3-(trifluoromethyl)benzyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-[3-azepan-1-yl-4-(trifluoromethyl)benzyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-(3-bromo-4-piperidin-1-ylbenzyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-[(7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4-piperidin-1-yl-3-(trifluoromethyl)benzyl]urea; 
     ethyl 1-[5-[({[(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)amino]carbonyl}amino)-methyl]-2-(trifluoromethyl)phenyl]piperidine-4-carboxylate; 
     N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-morpholin-4-yl-4-(trifluoromethyl)benzyl]urea;
 a tautomeric or stereoisomeric form of any of the foregoing compounds; and 
 a salt of any of the foregoing compounds. 
 
   
   
       34 . The method of  claim 28 , wherein the compound is N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea, in its tautomeric or stereoisomeric form, or a salt thereof. 
   
   
       35 . The method of  claim 28 , wherein the compound is N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-morpholin-4-yl-4-(trifluoromethyl)benzyl]urea, in its tautomeric or stereoisomeric form, or a salt thereof. 
   
   
       36 . A method of treating an inflammatory disorder or disease in a subject comprising administering to the subject an effective amount of a compound of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       n represents an integer of 0 to 6; 
       R 1  represents hydrogen or C 1-6  alkyl; 
       R 2  and R 3  together with the nitrogen atom to which they are attached, form a 3-8 membered saturated heterocyclic ring optionally interrupted by one or two atoms selected from the group consisting of oxygen, sulfur and nitrogen, 
       wherein said saturated heterocyclic ring has one or more substituents selected from the group consisting of halogen, benzyl, hydroxy, carboxy, amino, oxo, aminocarbonyl, C 1-6  alkoxycarbonyl, and C 1-6  alkyl optionally substituted by hydroxy, carboxy, C 1-6  alkoxy, or C 1-6  alkoxycarbonyl, or 
       R 2  represents C 2-6  alkenyl, C 2-6  alkynyl, or C 1-6  alkyl substituted by amino, hydroxy, C 1-6  alkylamino, or di(C 1-6  alkyl)amino; 
       R 3  represents hydrogen, C 2-6  alkenyl, C 2-6  alkynyl, or C 1-6  alkyl optionally substituted by amino, hydroxy, C 1-6  alkylamino, or di(C 1-6  alkyl)amino; and 
       R 4  represents hydrogen, halogen, C 1-6  alkylthio, C 1-6  alkyl optionally substituted by mono-, di-, or tri-halogen, or C 1-6  alkoxy optionally substituted by mono-, di-, or tri-halogen. 
     
   
   
       37 . The method of  claim 36 , wherein the inflammatory disorder or disease is selected from the group consisting of asthma and COPD. 
   
   
       38 . The method of  claim 36 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached, form a 5-7 membered saturated heterocyclic ring optionally interrupted by one or two atoms selected from the group consisting of oxygen and nitrogen. 
   
   
       39 . The method of  claim 36 , wherein the compound is selected from the group consisting of: 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-piperidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4-pyrrolidin-1-yl-3-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-pyrrolidin-1-yl-4-(-trifluoromethyl)benzyl]urea; 
     N-[4-azepan-1-yl-3-(trifluoromethyl)benzyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-[3-azepan-1-yl-4-(trifluoromethyl)benzyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-(3-bromo-4-piperidin-1-ylbenzyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
     N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-[(7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea; 
     N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4-piperidin-1-yl-3-(trifluoromethyl)benzyl]urea; 
     ethyl 1-[5-[({[(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)amino]carbonyl}amino)-methyl]-2-(trifluoromethyl)phenyl]piperidine-4-carboxylate; 
     N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-morpholin-4-yl-4-(trifluoromethyl)benzyl]urea;
 a tautomeric or stereoisomeric form of any of the foregoing compounds; and 
 a salt of any of the foregoing compounds. 
 
   
   
       40 . The method of  claim 36 , wherein the compound, its tautomeric or stereoisomeric form, or a salt thereof is N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-pyrrolidin-1-yl-4-(trifluoromethyl)benzyl]urea. 
   
   
       41 . The method of  claim 36 , wherein the compound is N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]-N′-[3-morpholin-4-yl-4-(trifluoromethyl)benzyl]urea, in its tautomeric or stereoisomeric form, or a salt thereof.